11-57712798-C-G

Position:

chr11-57712798-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM5BS1_SupportingBS2

The ENST00000278422.9(TMX2):c.180C>G(p.Asp60Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,614,072 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D60N) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

TMX2
ENST00000278422.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: 1.87

Variant links:

Genes affected

TMX2 (HGNC:30739): (thioredoxin related transmembrane protein 2) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, one transmembrane domain and a C-terminal ER-retention sequence. This protein is enriched on the mitochondria-associated-membrane of the ER via palmitoylation of two of its cytosolically exposed cysteines. [provided by RefSeq, Jan 2017]

TMX2 links:

ENSG00000288534 (HGNC:):

ENSG00000288534 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a topological_domain Extracellular (size 53) in uniprot entity TMX2_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in ENST00000278422.9

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-57712796-G-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00086 (131/152360) while in subpopulation NFE AF= 0.00159 (108/68038). AF 95% confidence interval is 0.00134. There are 0 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMX2	NM_015959.4 linkuse as main transcript	c.180C>G	p.Asp60Glu	missense_variant	1/8	ENST00000278422.9	NP_057043.1	Q9Y320-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMX2	ENST00000278422.9 linkuse as main transcript	c.180C>G	p.Asp60Glu	missense_variant	1/8	1	NM_015959.4	ENSP00000278422.4		Q9Y320-1
ENSG00000288534	ENST00000674060.1 linkuse as main transcript	n.33C>G		non_coding_transcript_exon_variant	1/20			ENSP00000501055.2		A0A669KB09

Frequencies

GnomAD3 genomes

AF:

0.000854

AC:

130

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00103

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00159

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00108

AC:

270

AN:

250628

Hom.:

AF XY:

0.00104

AC XY:

141

AN XY:

135558

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00168

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00120

AC:

1753

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

864

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.000498

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00141

Gnomad4 NFE exome

AF:

0.00137

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.000860

AC:

131

AN:

152360

Hom.:

Cov.:

AF XY:

0.000805

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00103

Gnomad4 NFE

AF:

0.00159

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000646

Hom.:

Bravo

AF:

0.000790

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00122

AC:

148

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00249

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0092

.;T

Eigen

Benign

0.055

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

N;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.28

N;N

REVEL

Benign

0.050

Sift

Benign

0.66

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.99

D;B

Vest4

0.47

MutPred

0.32

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

0.60

MPC

0.27

ClinPred

0.21

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.92

Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over